Centromedian-parafascicular Complex Research Articles

Human centromedian-parafascicular complex signals sensory cues for goal-oriented behavior selection

Experimental research has shown that the centromedian-parafascicular complex (CM-Pf) of the intralaminar thalamus is activated in attentional orienting and processing of behaviorally relevant stimuli. These observations resulted in the hypothesis that the CM-Pf plays a pivotal role in goal-oriented behavior selection. We here set out to test this hypothesis with electrophysiological recordings from patients with electrodes implanted in CM-Pf for deep brain stimulation (DBS) treatment of chronic neuropathic pain. Six patients participated in (1) an auditory three-class oddball experiment, which required a button press to target tones, but not to standard and deviant tones and in (2) a multi-speaker experiment with a target word that required attention selection and a target image that required response selection. Subjects showed transient neural responses (8–15Hz) to the target tone and the target word. Two subjects additionally showed transient neural responses (15–25Hz) to the target image. All sensory target stimuli were related to an internal goal and required a behavior selection (attention selection, response selection). In group analyses, neural responses were greater to target tones than deviant and standard tones and to target words than other task-relevant words that did not require attention selection. The transient neural responses occurred after the target stimuli but prior to the overt behavioral response. Our results demonstrate that in human subjects the CM-Pf is involved in signaling sensory inputs related to goal-oriented selection of behavior.

Parafascicular thalamic nucleus deep brain stimulation decreases NMDA receptor GluN1 subunit gene expression in the prefrontal cortex

The rodent parafascicular nucleus (PFn) or the centromedian-parafascicular complex of primates is a posterior intralaminar nucleus of the thalamus related to cortical activation and maintenance of states of consciousness underlying attention, learning and memory. Deep brain stimulation (DBS) of the PFn has been proved to restore arousal and consciousness in humans and to enhance performance in learning and memory tasks in rats. The primary expected effect of PFn DBS is to induce plastic changes in target neurons of brain areas associated with cognitive function. In this study, Wistar rats were stimulated for 20mins in the PFn following a DBS protocol that had previously facilitated memory in rats. NMDA and GABAB receptor binding, and gene expression of the GluN1subunit of the NMDA receptor (NMDAR) were assessed in regions related to cognitive functions, such as the prefrontal cortex and hippocampus. The results showed that PFn DBS induced a decrease in NMDAR GluN1 subunit gene expression in the cingulate and prelimbic cortices, but no significant statistical differences were found in the density of NMDA or GABAB receptors in any of the analyzed regions. Taken together, our findings suggest a possible role for the NMDAR GluN1 subunit in the prefrontal cortex in the procognitive actions of the PFn DBS.

Thalamocortical network activity enables chronic tic detection in humans with Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Deep brain stimulation (DBS) is an emerging therapy for severe cases of TS. We studied two patients with TS implanted with bilateral Medtronic Activa PC + S DBS devices, capable of chronic recordings, with depth leads in the thalamic centromedian–parafascicular complex (CM-PF) and subdural strips over the precentral gyrus. Low-frequency (1–10 Hz) CM-PF activity was observed during tics, as well as modulations in beta rhythms over the motor cortex. Tics were divided into three categories: long complex, complex, and simple. Long complex tics, tics involving multiple body regions and lasting longer than 5 s, were concurrent with a highly detectable thalamocortical signature (average recall [sensitivity] 88.6%, average precision 96.3%). Complex tics were detected with an average recall of 63.9% and precision of 36.6% and simple tics an average recall of 39.3% and precision of 37.9%. The detections were determined using data from both patients.

The human centromedian-parafascicular complex (CM/Pf) is involved in processing of behaviorally relevant auditory events

The human centromedian-parafascicular complex (CM/Pf) is involved in processing of behaviorally relevant auditory events

Effect of deep brain stimulation in rats selectively bred for reduced prepulse inhibition.

Sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle reaction (ASR), is disturbed in certain neuropsychiatric disorders, such as schizophrenia, obsessive compulsive disorder, and Tourette's syndrome (TS). Deep brain stimulation (DBS) of the centromedian-parafascicular complex (CM-Pf), globus pallidus internus (in rats the entopeduncular nucleus - EPN), and the ventral striatum (in rats the nucleus accumbens - NAC) has been used for treatment in TS. We tested whether DBS of these regions would alleviate breeding-induced low PPI in rats. Rats with breeding-induced low and high PPI were bilaterally implanted with electrodes in the CM-Pf, the EPN, or the NAC. After two weeks, they were stimulated or sham stimulated for epochs of 6 days (in the EPN with a current of 20% below the individual threshold for stimulation-induced side effects, in the NAC or CM-Pf with 100 μA and 150 μA). On the 6th day the rats were tested for PPI of ASR. Stimulation in the CM-Pf with 150 μA significantly alleviated PPI, while NAC stimulation was less effective. In PPI low rats electrode implantation in the EPN already improved PPI, while subsequent stimulation had no additional effect. Startle reaction of PPI low rats was not affected by stimulation of either region. The CM-Pf and the EPN are important for the modulation of sensorimotor gating in rats with breeding-induced low PPI. These rats may therefore be useful to further investigate the pathophysiological mechanisms of deficient sensorimotor gating and also mechanisms of action of DBS in these circumstances.

Effect of Deep Brain Stimulation on Levodopa-Induced Dyskinesias and Striatal Oscillatory Local Field Potentials in a Rat Model of Parkinson's Disease

BackgroundIn Parkinson's disease (PD) dyskinesias appear after long-term dopaminergic treatment. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) is a well-established treatment option for both PD symptoms and complications of medication. ObjectiveTo elucidate physiological mechanisms of the effect of DBS on levodopa-induced dyskinesias (LID) we investigated both DBS in the GPi and the centromedian-parafascicular complex (CM-Pf), which are part of an internal basal ganglia loop connecting with the dorsolateral striatum. In particular, we focused on changes of oscillatory activity in the dorsolateral striatum, which also presents the entrance region of the basal ganglia (BG). Methods6-Hydroxydopamine (6-OHDA) hemiparkinsonian (HP) rats and 6-OHDA lesioned HP rats with LID (HP-LID) were used to compare the effect of DBS in the entopeduncular nucleus (EPN, the equivalent to the human GPi) and the thalamic parafascicular nucleus (Pf, the equivalent of the human CM-Pf) on dyskinesias and neuronal oscillatory activity of selected frequency bands in the dorsolateral striatum on and off levodopa. ResultsIn HP-LID rats the relative beta and gamma power was lower, while relative theta power was higher as compared to HP rats. Chronic DBS of either the EPN or the Pf improved dyskinesia scores in HP-LID rats, and no differences in oscillatory activity were observed between groups. ConclusionsStimulation of the Pf has a specific impact on dyskinesias, which is similar to that found after EPN stimulation, and which is accompanied by changes of oscillatory activity.

Preferential networks of the mediodorsal nucleus and centromedian–parafascicular complex of the thalamus—A DTI tractography study

Distinct thalamic nuclei, like the mediodorsal (MD) nucleus and the centromedian/parafascicular complex (CM/Pf), are embedded in different basal ganglia-thalamocortical loops, which were shown to integrate cognitive and emotional aspects of human behavior. Despite well described connections on a microscopic scale, derived from tracing studies in animals, little is known about the intrinsic anatomical connections of these nuclei in humans. This lack of knowledge limits not only interpretation of functional imaging studies but also estimation of direct effects of deep brain stimulation which treats diseases as different as epilepsy or major depression. Therefore, non-invasive diffusion tensor imaging (DTI) studies are key to analyzing connectivity patterns and elaborate approaches to close this gap. For our study, we explored the structural connectivity of the MD thalamic nuclei and the CM/Pf complex towards five cortical and six subcortical regions by using a preferential fiber calculation. We found both thalamic nuclei to be preferentially associated to distinct networks: whereas the MD is preferentially connected to prefrontal and limbic cortical regions, the CM is linked to subcortical regions. The anterior insula was the only cortical region associated with the subcortical network of the CM and the cortical network of the MD comprised one subcortical hub, the caudate nucleus, suggesting an integrative role of these two regions. Adding to predescribed anatomical tract tracing connectivities in animal studies, our finding lends support to the existence of similar basal ganglia-thalamocortical circuits in humans and we could show a robust distinction of preferential connectivity for both thalamic nuclei.

Neuropsychiatric Outcome of an Adolescent Who Received Deep Brain Stimulation for Tourette's Syndrome

This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf) for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow-up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation.

Deep brain stimulation of the center median-parafascicular complex of the thalamus has efficient anti-parkinsonian action associated with widespread cellular responses in the basal ganglia network in a rat model of Parkinson's disease.

The thalamic centromedian-parafascicular (CM/Pf) complex, mainly represented by Pf in rodents, is proposed as an interesting target for the neurosurgical treatment of movement disorders, including Parkinson's disease. In this study, we examined the functional impact of subchronic high-frequency stimulation (HFS) of Pf in the 6-hydroxydopamine-lesioned hemiparkinsonian rat model. Pf-HFS had significant anti-akinetic action, evidenced by alleviation of limb use asymmetry (cylinder test). Whereas this anti-akinetic action was moderate, Pf-HFS totally reversed lateralized neglect (corridor task), suggesting potent action on sensorimotor integration. At the cellular level, Pf-HFS partially reversed the dopamine denervation-induced increase in striatal preproenkephalin A mRNA levels, a marker of the neurons of the indirect pathway, without interfering with the markers of the direct pathway (preprotachykinin and preprodynorphin). Pf-HFS totally reversed the lesion-induced changes in the gene expression of cytochrome oxidase subunit I in the subthalamic nucleus, the globus pallidus, and the substantia nigra pars reticulata, and partially in the entopeduncular nucleus. Unlike HFS of the subthalamic nucleus, Pf-HFS did not induce per se dyskinesias and directly, although partially, alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced forelimb dyskinesia. Conversely, L-DOPA treatment negatively interfered with the anti-parkinsonian effect of Pf-HFS. Altogether, these data show that Pf-DBS, by recruiting a large basal ganglia circuitry, provides moderate to strong anti-parkinsonian benefits that might, however, be affected by L-DOPA. The widespread behavioral and cellular outcomes of Pf-HFS evidenced here demonstrate that CM/Pf is an important node for modulating the pathophysiological functioning of basal ganglia and related disorders.

Núcleos intralaminares posteriores del tálamo y procesos cognitivos

The parafascicular nucleus in rats and the centromedian parafascicular complex in primates and other mammals are the so-called posterior intralaminar nuclei (pIL) of the thalamus. Like the ascending reticular activating system and the basal ganglia-thalamocortical circuit, the pIL nuclei are part of the brain arousal systems.To describe and analyze different animal and human studies suggesting that the pIL could also be part of a neuro-physiological subcortical system related to cognitive processes as attention, learning and memory.Both parafascicular nucleus lesion studies in rats and neuropathological and neuroimaging reports in humans, indicate a relationship between the degeneration of pIL neurons and the cognitive deficits observed in learning and memory tasks in animals and also in several human neurological diseases and in consciousness disorders.Considering its neuroanatomical, neurophysiological and functional characteristics, the pIL can be considered excellent candidates for investigating cognitive processes in the field of psychobiology and clinical neurology.

Relative preservation of thalamic centromedian nucleus in parkinsonian patients with dystonia

To determine whether variable thalamic degeneration in Parkinson's disease (PD) contributes to less drug responsive clinical features. Formalin-fixed thalami from longitudinally followed patients with PD and early dystonia (N = 6), early falls (N = 5) or no dystonia or falls (N = 6) and age-matched controls without neuropathology (N = 10) were serially sectioned, stained, and analyzed. Neurons in the centromedian parafascicular (CM-Pf) nucleus were quantified using the optical disector method and analysis of variance with post hoc testing used to determine variability in neurodegeneration between groups. Patients with PD were confirmed to have significant neurodegeneration in the CM-Pf complex, with no difference in the degree of neurodegeneration between patients with PD with early falls compared with patients with no history of falls or dystonia. In contrast, patients with PD with early dystonia had significantly less neurodegeneration of the CM but not the Pf than patients without this feature. Preservation of the CM in patients with PD with early dystonia would result in a relative increase in CM activity through the direct basal ganglia pathway and increased primary motor cortex activity. Overall this data provides evidence for pathway-specific neurodegeneration as an underlying feature of the clinical variability observed in patients with PD.

Internal Pallidal and Thalamic Stimulation in Patients With Tourette Syndrome

Tourette syndrome (TS) is thought to result from dysfunction of the associative-limbic territories of the basal ganglia, and patients with severe symptoms of TS respond poorly to medication. High-frequency stimulation has recently been applied to patients with TS in open studies using the centromedian-parafascicular complex (CM-Pf) of the thalamus, the internal globus pallidus (GPi), or the anterior limb of the internal capsule as the principal target. To report the effect of high-frequency stimulation of the CM-Pf and/or the GPi, 2 associative-limbic relays of the basal ganglia, in patients with TS. Controlled, double-blind, randomized crossover study. Medical research. Three patients with severe and medically refractory TS. Bilateral placement of stimulating electrodes in the CM-Pf (associative-limbic part of the thalamus) and the GPi (ventromedial part). Effects of thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation on neurologic, neuropsychological, and psychiatric symptoms. A dramatic improvement on the Yale Global Tic Severity Scale was obtained with bilateral stimulation of the GPi (reduction in tic severity of 65%, 96%, and 74% in patients 1, 2, and 3, respectively). Bilateral stimulation of the CM-Pf produced a 64%, 30%, and 40% reduction in tic severity, respectively. The association of thalamic and pallidal stimulation showed no further reduction in tic severity (60%, 43%, and 76%), whereas motor symptoms recurred during the sham condition. No neuropsychological, psychiatric, or other long-term adverse effect was observed. High-frequency stimulation of the associative-limbic relay within the basal ganglia circuitry may be an effective treatment of patients with TS, thus heightening the hypothesis of a dysfunction in these structures in the pathophysiologic mechanism of the disorder.

Deep brain stimulation of the thalamus as a treatment of intractable Tourette Syndrome

Gilles de la Tourette Syndrome (TS) is a chronic neuropsychiatric disorder characterised by multiple motor tics and one or more phonic (vocal) tics. 90% of patients have comorbid disorders including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), self-injurious behaviours, depression and anxiety. Treatment of TS includes typical and atypical neuroleptics, alpha-adrenergic agonists, benzo-diazepines and behavioural interventions. Recently, a number of case reports and case series have demonstrated that deep brain stimulation (DBS) targeting the centromedian-parafascicular complex (CM-PF) of the thalamus, globus pallidus or internal capsule and nucleus accumbens may have beneficial effects on TS. The best evidence currently exists for the safety and efficacy of DBS targeted to the thalamus. Here, we report on the efficacious treatment of a 30 year old man with a 15 years history of medication resistant TS with a predominant complex, self-injurious motor tic of violent pounding his chin with the left hand (YGTSS 77/100), comorbid OCD (Y-BOCS 24/40) and moderate depression (HAM-D: 28) in bipolar disorder with bilateral DBS placed within the thalamus. Neuropsychological testing and positron emission tomography (PET) were performed before and after the start of treatment. Following the guidelines on DBS for neuropsychiatric disorders and the recent recommendations for DBS in TS, the local DBS-assessment committee ensured that all suggested medical, neurological and psychiatric criteria were met. After local ethics committee approval and written informed consent, two DBS electrodes were placed in the CM-PF complex of the thalamus under general anaesthesia.

Antinociceptive effects of brain rewarding system in the developing rabbit: behavioral and electrophysiological analysis

The modulating effects of electrical stimulation (ES) in the reward sites (RSs) of the hypothalamus and adjacent brain areas on the defensive reaction (DR) in response to peripheral noxious stimulation (PNS) and on evoked potentials (EPs) recorded in the thalamic centromedian–parafascicular complex (CM-Pf) to the same PNS have been investigated in 20–40-, 41–60-day old and 3–5-month old rabbits. Previously, RSs were identified by the method of intracranial self-stimulation (ICSS). Behavioral and electrophysiological testings successively performed on each rabbit first awake and then anaesthetized have revealed the ES in all investigated RSs to inhibit DR and EPs. These effects were not observed if the stimulating electrode tip was localized in emotionally neutral brain sites. In behavioral testings, the antinociceptive effect of rewarding stimulation was positively correlated with the ICSS intensity in given brain sites regardless of the age of the rabbits. In electrophysiological testings, a similar dependence of nociceptive EPs inhibition on emotional values of stimulated brain sites (determined as a rate of lever pressings during ICSS) was discovered only in 20–40-day and 3–5-month old rabbits. Stimulation of low emotional value RSs (low rate (LR)-rabbits) exerted a weaker inhibitory influence in 3–5-month old rabbits in comparison with 20–40- and 41–60-day old rabbits both in behavioral and electrophysiological testings. The weakest antinociceptive effect of rewarding stimulation among the rabbits with a high rate of lever pressings (HR-rabbits) was found in 41–60-day olds in electrophysiological testings. In 41–60-day old rabbits, we have observed a discrepancy between the behavioral analgesia and its electrophysiological correlates. It may be suggested that the observed peculiarities of antinociceptive influences produced by RSs ES are determined by the age factors of neurotransmitter brain systems.

A di-synaptic projection from the superior colliculus to the head of the caudate nucleus via the centromedian-parafascicular complex in the cat: an anterograde and retrograde labeling study

Centromedian-parafascicular (CM-Pf) complex of the thalamus receives inputs from the superior colliculus (SC). The CM-Pf neurons, in turn, project to the neostriatum. In order to establish a circuitry that the efferent terminals of SC neurons make direct synaptic contacts with thalamostriatal neurons in the CM-Pf complex, the anterograde tracer (biocytin) was injected into the unilateral SC and the retrograde tracer (wheat germ agglutinin conjugated to horseradish peroxidase, WGA–HRP) into the ipsilateral head of the caudate nucleus of the cat. The anterogradely labeled SC fibers and their terminals and retrogradely labeled CM-Pf neuronal elements were examined under light and electron microscope. At the light micrsocopic level, biocytin-labeled terminal-like varicosities were observed densely in the latero-dorsal part of the CM and the dorsal part of the Pf lateral to the fasciculus retroflexus. These varicosities were often in close proximity to HRP-labeled somata and dendrites of CM-Pf neurons. Electron microscopic analysis revealed that the biocytin-labeled synaptic boutons contained mainly round synaptic vesicles and established asymmetrical synaptic contacts with retrogradely labeled thalamostriatal neuronal elements, including perikarya, and small and large dendrites. In addition, anterogradely labeled terminals made synaptic contacts with unlabeled somata, small and large dendrites, and spines as well as profiles containing synaptic vesicles. These vesicle-containing profiles were considered to be pre-synaptic elements contacting on thalamostriatal neurons or the vesicle-containing dendrites of local circuit neurons. These results demonstrate that the neurons of the CM-Pf complex of the thalamus is involved in a di-synaptic tecto-striatal circuit.

Overlapping territories between the thalamostriatal and nigrothalamic projections in cats.

Fluorescent tracers were injected into different regions of the caudate nucleus and HRP-WGA in the substantia nigra of the cat in order to analyse the thalamic distribution of retrogradely labelled thalamostriatal neurones and anterogradely labelled nigrothalamic terminals within the thalamus. Overlapping thalamic territories between the thalamostriatal neurones projecting to areas of the caudate nucleus and the nigrothalamic connections were observed in the rostral nuclei of the central thalamic group (ventral anterior nucleus, ventral anterior-ventral lateral complex and ventral medial nucleus) and, more restricted, in the rostral (rhomboid, paracentral, ventral lateral, dorsal mediodorsal nuclei) and caudal intralaminar nuclei (centromedian-parafascicular complex). This study provides evidence of the existence of thalamic areas in which the input and output of the basal ganglia converge.

Overlapping territories between the thalamostriatal and nigrothalamic projections in cats.

Fluorescent tracers were injected into different regions of the caudate nucleus and HRP-WGA in the substantia nigra of the cat in order to analyse the thalamic distribution of retrogradely labelled thalamostriatal neurones and anterogradely labelled nigrothalamic terminals within the thalamus. Overlapping thalamic territories between the thalamostriatal neurones projecting to areas of the caudate nucleus and the nigrothalamic connections were observed in the rostral nuclei of the central thalamic group (ventral anterior nucleus, ventral anterior-ventral lateral complex and ventral medial nucleus) and, more restricted, in the rostral (rhomboid, paracentral, ventral lateral, dorsal mediodorsal nuclei) and caudal intralaminar nuclei (centromedian-parafascicular complex). This study provides evidence of the existence of thalamic areas in which the input and output of the basal ganglia converge.

An electron microscopic tracer study of the projections from entopeduncular nucleus to the ventrolateral nucleus of the rat

The entopeduncular (EP) nucleus is considered to be the major outflow nucleus of the basal ganglia (BG). The anterograde tracer dextran biotin was injected into EP to investigate its connections with the thalamus. Terminals from EP were found in the ipsilateral ventroanterior-ventrolateral (VAL) and ventromedial thalamic nuclei (VM), lateral habenular and centromedian-parafascicular complex. Electron microscopy of the terminals in VAL/VM revealed densely labelled small synapses that had prominent post-synaptic densities and round vesicles. Synapses were observed onto dendrites and dendritic spines but not onto other synapses or somas. No symmetrical synapses with pleomorphic vesicles were labelled. It is concluded that the synaptic contacts between EP and thalamus are Gray type 1. These findings have implications regarding current theories of BG pathophysiology.

Nerve cell loss in the thalamic centromedian-parafascicular complex in patients with Huntington's disease.

The centromedian-parafascicular complex represents a nodal point in the neuronal loop comprising striatum--globulus pallidus--thalamus--striatum. Striatal neurone degeneration is a hallmark in Huntington's disease and we were interested in estimating total neurone and glial number in this thalamic nuclear complex. Serial 500-microns-thick gallocyanin-stained frontal sections of the left hemisphere from six cases of Huntington's disease patients (three females, three males) and six age- and sex-matched controls were investigated applying Cavalieri's principle and the optical disector. Mean neurone number in the controls was 646,952 +/- 129,668 cells versus 291,763 +/- 60,122 in Huntington's disease patients (Mann-Whitney U-test, P < 0.001). Total glial cell number (astrocytes, oligodendrocytes, microglia, and unclassifiable glial profiles) was higher in controls with 9,544,191 +/- 3,028,944 versus 6,961,989 +/- 2,241,543 in Huntington's disease patients (Mann-Whitney U-test, P < 0.021). Considerable increase of fibrous astroglia within the centromedian-parafascicular complex could be observed after Gallyas' impregnation. Most probably this cell type enhanced the numerical ratio between glial number and neurone number (glial index: Huntington's disease patients = 24.4 +/- 8.1; controls = 15.0 +/- 5.2; Mann-Whitney U-test, P < 0.013). The neurone number in the centromedian-parafascicular complex correlated negatively, although statistically not significantly, with the striatal neurone number. This lack of correlation between an 80% neuronal loss in the striatum and a 55% neurone loss in the centromedian-parafascicular complex points to viable neuronal circuits connecting the centromedian-parafascicular complex with cortical and subcortical regions that are less affected in Huntington's disease.

Noncholinergic, nonadrenergic cortical vasodilatation elicited by thalamic centromedian-parafascicular complex.

The centromedian-parafascicular complex (CMPf) of the intralaminar thalamus was stimulated in anesthetized, ventilated rats, and cerebral cortical perfusion was continuously measured using laser Doppler flowmetry. Stimulation led to a frequency- and intensity-dependent increase in cortical perfusion (vasodilatation). The maximum response was seen at a rate of 200/s, and studied at 150 microA, was a 120 +/- 27% (n = 6) increase in flow. The mean time from the initiation of stimulation to a change in the cerebral blood flow measured by laser Doppler flowmeter signal was 800 +/- 100 ms (n = 13). The response to electrical stimulation was not blocked after high spinal cord section. Chemical stimulation of the CMPf neurons by microinjection of carbachol led to a 98 +/- 15% (n = 4) increase in flow. The response to electrical stimulation was not blocked by the muscarinic antagonist scopolamine (1 mg/kg) or by the nicotinic antagonist mecamylamine (4 mg/kg). It was also unaffected by the beta-adrenoceptor antagonist propranolol (1.5 mg/kg). These data add to understanding of the CMPf cerebral vasodilator response by demonstrating a robust stimulus-locked change in cortical perfusion that does not involve a cholinergic or adrenergic mechanism. It is also shown to be frequency and intensity dependent, consistent with a functioning physiological system, and has a rapid onset consistent with a primarily neurally mediated phenomenon. Furthermore, it is elicited by pathways that may possibly be entirely within the central nervous system and is due to activation of cell bodies within the region.